Summary

• The recommended dose of XARELTOfor the initial treatment of acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) is 15 mg taken orally twice daily (BID) with food for the first 21 days. After this initial treatment period, the recommended dose of XARELTOis 20 mg taken orally once daily with food, at approximately the same time each day.¹
• The recommended dose of XARELTO for the reduction in the risk of recurrence of DVT and/or PE in patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months is 10 mg taken orally once daily with or without food.¹
• Dosing for patients being reinitiated on XARELTOafter interruption of therapy during the initial treatment phase should be based on your clinical judgment of the patient’s risk at the time of reinitiation. No recommendation is available for this clinical situation.

CLINICAL STUDIES

The selection of the dosing regimen in the EINSTEIN-DVT and EINSTEIN-PE trials^2,3 (XARELTO 15 mg BID for 3 weeks, followed by 20 mg once daily), and the dosing regimen in the EINSTEIN-Extension trial² (XARELTO 20 mg once daily) were based primarily on the results of the dose-ranging venous thromboembolism (VTE) treatment phase 2 trials: the ODIXa-DVT study⁴ and the EINSTEIN-DVT Dose-Ranging study⁵. Both dose-ranging VTE treatment phase 2 trials suggest the optimal dosing regimen consists of a BID administration of 15 mg for the initial 3-week treatment phase followed by once daily administration of 20 mg for the subsequent treatment period in the EINSTEIN program.

ODIXa-DVT study

• The initial BID dosing regimen used in the EINSTEIN-DVT and EINSTEIN-PE trials was based on the ODIXa-DVT study, which evaluated improvement in thrombotic burden at three weeks for each of four double blinded doses of XARELTO 10 mg, 20 mg, or 30 mg BID OR 40 mg once daily, with food and open-label standard anticoagulation (subcutaneous [SC] enoxaparin 1 mg/kg BID (for at least 5 days) followed by vitamin K antagonist (VKA)) for treatment of acute proximal DVT.⁴
• The primary efficacy endpoint (thrombus score improvement by at least four points without VTE recurrence or VTE-related death) occurred in 53%, 59.2%, 56.9%, and 43.8% of the respective XARELTO dose groups and in 45.9% of the enoxaparin/VKA group.⁴
• Major bleeding rates were 1.7%, 1.7%, 3.3%, and 1.7% in the respective XARELTO dose groups and 0% in the enoxaparin/VKA group. Rates of any bleeding were 5.0%, 9.4%, 10.7%, and 11.6% in the respective XARELTO dose groups and 6.3% in the enoxaparin/VKA group.⁴
• Pharmacokinetic modeling demonstrated that higher trough concentrations are observed with a BID XARELTO dosing regimen in comparison with a once daily dosing regimen, and may provide an intensified anticoagulant effect during initial treatment in patients with a DVT or PE.⁴

EINSTEIN-DVT Dose-Ranging study

• The EINSTEIN-DVT Dose-Ranging study was a Phase II dose-ranging study that compared double blinded oral XARELTO 20, 30, or 40 mg once daily versus open-label parenteral unfractionated heparin (started with 5,000-IU bolus and 1,250-IU/hour infusion) or low molecular weight heparin (SC tinzaparin 175 IU/kg once daily or SC enoxaparin 1.5 mg/kg once daily or 1 mg/kg BID) followed by an oral VKA for treatment of symptomatic acute DVT. Treatment was continued for 12 weeks.⁵
• The primary efficacy endpoint (composite of symptomatic recurrent DVT, symptomatic fatal or nonfatal PE, and asymptomatic deterioration in the thrombotic burden as assessed by comparison of ultrasound or perfusion lung scan at day 84 with baseline) occurred in 6.1%, 5.4%, and 6.6% of the respective XARELTO dose groups and 9.9% in the heparin/VKA group.⁵
• The primary safety outcome (composite of major bleeding and clinically relevant non-major bleeding up until 2 days after the end of the treatment) occurred in 5.9%, 6.0%, and 2.2% of the respective XARELTO dose groups and 8.8% in the heparin/VKA group.⁵

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 20 March 2024.